Our laboratory has explored the determinants of response to diuretics in both normal conditions and in diseases in which response is altered. Data focused on patients with heart failure showing delayed absorption of furosemide after oral dosing, normal quantitative absorption, normal renal clearance, and suppressed response relative to amounts of diuretic reaching the site of action. Future studies will examine patients with renal insufficiency, particularly addressing the question of whether response of individual nephrons to amounts of diuretic reaching them is normal. We will also study patients with nephrotic syndrome addressing whether or not binding of diuretic to urinary protein is an important contributor to diuretic resistance in these patients. Our laboratory has also studied the renal role of prostaglandins, exploring effects of nonsteroidal anti-inflammatory drugs on renal function. Prior studies by us have questioned the putative renal sparing effect of sulindac. We wish to explore this area further with pharmacokinetic and pharmacodynamic studies in patients with cirrhosis. We have also assessed the effects of indomethacin in patients with renal insufficiency and in preliminary studies found it to transiently and reversibly decrease renal perfusion. We wish to determine whether continuous suppression of renal prostaglandins causes persistent effects. We have learned the technique of microperfusion of isolated nephron segments to assess handling of nonsteroidal anti-inflammatory (and other) drugs by the kidney. Preliminary data have shown substantial secretion of indomethacin by the proximal tubule and considerable formation of indomethacin glucuronide. It would appear that transport of this drug may represent a two step process. We propose further pursuit of these questions.